Guanidene derivatives for coccidiosis

ABSTRACT

Animals are treated by oral administration of a 1,2,3-tris((phalobenzylidene)amino)guanidine or its hydrochloride salt to allow maximum normal growth of the animals by the control of protozoan organisms and mitigate against the attack of gastrointestinal parasites. The guanidine compound is of the formula:

United States Patent Inventor Appl. No. Filed Patented Assignee GUANIDENE DERIVATIVES FOR COCCIDIOSIS 11 Claims, No Drawings u.s. Cl 424/326 Int. Cl A6lk 27/00 Field 0! Search 424/3 26 References Cited UNITED STATES PATENTS 3/1970 Badcock..'..... 424/326 Primary Examiner-Sam Rosen Anomeys-Griswold and Burdick, S. Preston Jones and C.

Kenneth Bjork ABSTRACT: Animals are treated by oral administration of a l,2,3-tris[ p-halobenzylidene )amino lguanidine or its hydrochloride salt to allow maximum normal growth of the animals by the control of protozoan organisms and mitigate against the attack of gastrointestinal parasites. The guanidine yns iief ihief t wherein X is chlorine or bromine.

1 GUANIDENE DERIVATIVES FOR COCCIDIOSIS BACKGROUND OF THE INVENTION This invention relates to animal husbandry and more particularly to methods and compositions adapted to be employed to allow maximum normal growth of animals, for controlling protozoan organisms and for mitigating against the attack of gastrointestinal parasites. The term animal as used herein is employed in context of its general definition and is meant to include fowl, particularly domesticated fowl; i.e. poultry.

lt is an object of the present invention to provide a new and improved practice for raising and benefiting animals such as rabbits, lambs, calves, chickens, guinea fowl, pigeons, geese, turkeys and other domesticated animals and to provide a new and improved method and composition for mitigating against and protecting animals from the attack of gastrointestinal parasites. Still another object is to provide a method and composition which may be employed prophylactically to protect animals from the attack of gastrointestinal parasites without adversely affecting the normal physiological processes.

SUMMARY OF THE lNVENTlON chlorobenzylidene )aminolguanidine; chlorobenzylidene)aminolguanidine, hydrochloride; 1,2,3-

wherein X represents chlorine or bromine.

Representative guanidine compounds include l,2,3-tris[(pl(P- tris[(p-bromobenzylidene)aminolguanidine, and 1,2,3- trisl (p-bromobenzylidene )aminolguanidine, hydrochloride.

The practice allows maximum normal growth of the animals and protects the animals from parasitic diseases of the gastrointestinal tract and particularly from coccidiosis. Further, the practice protects the animals from mixed coccidial infections and from the various strains of the same species of coccidial organism and particularly from the various strains of Eimen'a tenella, Eimeria necatrix, Eimeria acervulina, Eimeria maxima and Eimeria bruneui. Also, while protecting the animals from coccidiosis, the practice allows the protected animals which are exposed to the coccidial infection to develop acquired immunity to the disease.

The guanidine-type compounds are crystalline solids and are adapted to be administered to animals. The compounds are not repellent to animals and can be employed in admixture with grain rations, animal feeds or drinking water. They can be administered continuously or intennittently in dosages sufficient to allow maximum normal growth and utilization of feed and to protect the animal from the attack of gastrointestinal parasites without adversely affecting the normal physiological processes, or without imparting any unpalatable characteristic to animal flesh.

The oral administration of an effective dosage of the compounds is essential and critical for the practice of the present invention. In general, good results are obtained when the animals are fed a daily dosage of from about three to about 1,000 parts of the compounds per million parts of dietary intake, and preferably from about to about 250 parts per million parts of dietary intake. Where danger of reexposure to the attack of intestinal parasites from contaminated feed or surroundinss is 5 r s ar tai ed M 99 lisaq mals are fed a daily dosage of about 60 parts or more per million parts of dietary intake. By the term "dietary intake" is meant grain rations, animal feeds and/or drinking water.

The method of the present invention can be carried out by the oral administration of the unmodified compounds. However, the present invention also embraces the employment of a liquid, powder, mash, pellet, capsule or other animal food containing said compounds. ln such usage, the compounds can be modified with one or more of a plurality of additaments including water, ethanol, skim milk, edible oils, propylene glycol, syrups, grain rations, surface active dispersing agents such as the liquid and solid emulsifying agents and solid carriers such as edible powders and commercial animal feeds, concentrates or supplements. By commercial animal feeds, concentrates or supplements" are meant the partial and complete animal feeds containing desirable amounts of minerals, vitamins, antioxidants, antibiotics and growth stimulants. Further, the compositions are adapted to be fed to animals to supply the desired dosage of active agents, or to be employed as concentrates and subsequently diluted with additional carrier to produce the ultimate compositions.

The exact concentration of the compounds to be employed in the compositions can vary provided that enough of the composition is ingested by the animal so as to provide the required internal amount of active ingredient as set forth hereinbefore. For example, where direct administration to the individual animal is preferred, liquid or solid compositions containing from 5 to 98 percent by weight of the agents conveniently are employed to supply the desired dosage. Where the compounds are provided as a constituent of the principal food ration, satisfactory results are obtained with food rations containing a minor but effective amount of the compounds. The exact amounts of the compounds in the ration are dependent upon the food consumption and feeding habits of the animal concerned. With most animals, the required dosage can be supplied with mash compositions containing from 0.001 to 0.] percent by weight of active material when fed as the principal food ration. The compounds can also be furnished in the drinking water by conventional formulation techniques.

In liquid compositions to be employed as concentrates, the active agents can be present in a concentration of from 5 to 98 percent by weight. Preferred concentrate compositions oftentimes contain two or more percent by weight of a liquid or solid surface active agent.

Liquid compositions containing the desired amount of the ln the preparation of solid feed compositions, the comthe compounds can be dissolved in an organic solvent such as alcohol or acetone and the resulting mixture dispersed in an animal feed which is then dried to remove the solvent. The

compounds can also be dispersed in an edible oil such as coconut, olive, cottonseed or peanut oil and the resulting mixtures dispersed in the feed. These edible oil compositions can contain one of the aforementioned emulsifying materials as a dispersing agent.

In addition to poultry feeds containing a minor amount of the guanidine compound as an effective anticoccidial agent, there are provided in accordance with an additional aspect of this invention poultry feed supplement compositions wherein the heretofore described compound is intimately dispersed in,

reflects the difference in the challenge necessary for each coccidiai organism to give a 100 percent degree of pathogenicity. Another flock of birds is left untreated and uninoculated to serve as an uninfected check. Seven days following the initiation of the diets, the birds are sacrificed, autopsied and an examination made to determine thepercent control of coccidiosis and of the coccidial organisms. The percent control of coccidiosis and the coccidial organisms obtained in the evalua- -tions at the indicated percent by weight of guanidine compound in the diets as well as in the infected and uninfected checks is set forth below in table I. i

TABLE I Percent control of coeeidiosis and Percent the coccidial organisms by weight of agent Etmeria Eimeria Eimeria Agent employed in diet in feed temlla necatrlz acervulina 0. 05 100 100 91 1,2,3-trls[(p-ehlorobenzylidene) amino] 0. 025 100 100 89 guanidine. 0. 0125 100 100 83 0. 0062 92 0.05 97 100 86 1,2,3-tri (p-chlorobenzylidene)smino] 0. 025 84 100 92 guani no, hydrochloride. 0. 0125 84 100 94 0. 0002 o 1 2 am b lid 1 0 I i s romobens one amino 7 summit; y 0. 0125 11 100 82 0. 0062 0. 05 I 100 100 so l,2,3-tris[(p-bromobenzylidene)amino] 0. 025 83 100 94 gusnidine, hydrochloride. 8. 365g 81 100 Infected check (Control)-...' o S '6; Uninfected check (Control) 0 1 All birds heavily infected with eoccidial organisms. I N o coecidial organisms or disease.

then added to the remainder of the feed with adequate mixing. EXAMPLE 2 The coccidiostat compounds described hereinabove may be formulated into feed supplement compositions containing from about 0.25 percent to about percent by weight of the active ingredient. it will, therefore, be appreciated that the preferred supplement concentration will depend to a large extent on the final use level desired. With the compounds of this invention, feed supplement compositions containingfrom.

' substance in the finished feed. The finished feed is one that contains a source of fat, protein, carbohydrate, minerals, vitamins and other nutritional factors.

' The following examples will serve to further illustrate the present invention but are not meant to limit it thereto.

EXAMPLE 1 l ,2,3-tris[ (p-chlorobenzylidene )amino]guanidine; 1,2,3- trisl(p-chlorobenzylidene)aminolguanidine, hydrochloride;

l,2,3-tris[(p-bromobenzylidene)aminolguanidine and l,2,3- trisl(p-bromobenzylidene)amino1guanidine, hydrochloride are separately dispersed in commercial poultry mash to produce animal feed compositions containing predetermined amounts of one of the guanidine compounds. Portions of these compositions and unmodified mash are fed as a sole feed ration to flocks of chickens ofthe same history and past environment which are about l7 days old. One day after the diets are begun, 50,000 sporulated Eimeria necatrinoocysts or 200,000

sporulated Eimeria tenella oocysts or 5,000,000 sporulated Eimeria aeervulina oocysts are introduced directly into' the .crop of the birds. Thed ifference in the inoculation rate Portions of the feed compositions as described in example I and unmodified poultry feed were fed as a sole ration to groups of chickens of the same history and past environment. Each test group consists of 30 birds which are about l6 days old. The birds are maintained on wire in battery brooders according to conventional sanitary poultry practices. One day following the initiation of the diets, 200,000 sporulated oocysts of a mixed culture of Eimeria tenella oocysts and El'men'a necam'x oocysts are introduced directly into the crop of each bird. Another 30-bird flock was left untreated and uninoculated to serve as an uninfected check.

During the interval between the fourth and eleventh days following the initiation of the diets, the birds are observed for bloody diarrhea and gastrointestinal hemorrhage attributable to coccidial disease and the attack of the coccidial organisms. Hemorrhage scores are made with 0 for no hemorrhage, l for slight hemorrhage, 2 for moderate hemorrhage, 3 for severe hemorrhage and 4 for very severe hemorrhage.

Following the inoculation, the birds are observed for mortality, and any birds which die are autopsied to ascertain whether or not their death was attributable to coccidial disease and the attack of the coccidial organisms. The hemorrhage scores for the treated birds are also compared with the hemorrhage scores for the infected checks and the percent control of hemorrhage determined. The results obtained in these operations are set forth in table II.

TABLE II b by weight Hemorrhage Agent Employed in Diet of agent in feed Scores in feed l.2.3-trisl( P- hlorobenzyiidenehminolguanidine 0.05 0 0.025 0 0 l,2,3-tris[(p-chlorobenzylidenehminolguanidine.

hydrochloride 0.05 0

M25 0.025 100 0.0125 I00 '"9 Infected check 0 (Control) i Mencmmmolgunmdine 0.05 0 uninfecmd check 0 (control) (2) 0.02s 0 o.o|2s l LZJ-trisHp-bromobenzyli. All hirdl showed very severe hemorrhage idene)amino]guanidine, hydrochloride 0.05 0 2. No hemorrhage 0.02s 0 0.012: (a) infected check none (control) 4 EXAMPLE 4 Uninl'ected check none (control) 0 lo Twenty-five percent by weight of each of l,2,3-tns[(pa. onechicken had slight hemorrahage chlombenzylidene)aminolguanidine; l.2. ri l(pchlorobenzylidene)amino1guanidine, hydrochloride; 1,2,3- I trisl(p-bromobenzylidene)aminolguanidine and l,2,3-tris[(p- EXAMPLE 3 bromobenzylidene)aminoIguanidine, hydrochloride are in asimilar operation, each of the compounds l,2,3-tris[(psepa'ately ground with 75 pans of funer's earth F chlombenzylidene)aminolguanidine; 1,234.48? dispersible concentrates. Portions of the latter compositions chlorobenzylidene)aminolguanidine, hydrochloride; 1,2,3- qispel'sed in d? P f f mash lJl'odllce tris[(p-bromobenzylidene)amino1guanidine and l,2,3-tris[(p- 2O mefilliaied feed wmlmsmom3 Fontalnmg F y bromobenzylidene)aminolguanidine, hydrochloride were fed weight Ofthe S as constituents of animal feed to -bird groups of chickens The medicated feed compositions and unmdffied slanlng and the chickens subsequenfly inoculated with a mixed mash are fed as a sole feed ration to groups of chickens of the ture of various species of coccidia. in such operations, the insfime y and P enlflwnmem- Each Such test group oculum employed per bird contained sporulated coccidial oo- $1, 9?! 9 three ds Pi 2 195 of .38? Fortyelgm cysts in number and type as follows: 200,000 Eimeria tenella, 50,000 Eimeria necam'x, and 5,000,000 Eimeria acervulina. The results obtained in these operations are set forth in table III;

hours after the initiation of the diets, 80,000 sporulated Eimeria tenella oocysts are introduced directly into the crop of each bird. After the end of the fifth and seventh day following the int mation tl i e @rdsare weighed and the average weight TABLE IV Average weight per test Percent group in grams at the Percent control 01 indicated intervals iollowweight coccidiosis lng inoculation increase of and test coccidial Active agent at dosage of 0.05 weight percent of feed 0 day 5 days 7 days group organisms 1,2,3-trls[(p-chiorobenzylidene)amino guanidine 426 667 762 80 0 1,2,3-tris[(p-chlorobenzylidene)amino guanidine, hydrochloride. 424 659 740 75 97 1,2,3-tris[(p-bromobenzylidene)amino guanidine 395 601 687 7 84 1,2,3-tris[(pbromobenzylidene)amino guanidine, hydrochloride. 406 642 729 80 100 Uniniected checks (Control) 412 625 697 69 (0 Infected checks (Control) 420 570 592 41 1 No coccidial organisms or disease.

1 All birds heavily infected with coccidial organisms.

for each test group, determined. Another group of birds was 45 left untreated and uninoculated to serve as an uninfected check. The average weights of each test group at the aforementioned intervals, the percent weight increase and percent control of coccidiosis for each test group are set forth in table EXAMPLE 5 In a similar operation, portions of the concentrates of example 4 are dispersed in commercial poultry starting mash to produce medicated feed compositions containing 0.025 percent by weight of one of the agents.

These medicated feed compositions and unmodified starting mash are fed as a sole feed ration to groups of chickens of the same history and past environment. Each such test group consisted of three birds which are 2 weeks of age. Forty-eight hours after the initiation of the diets, 5,000,000 sporulated Eimeria acervulina oocysts are introduced directly into the crop of each bird. After the end of the fifth and seventh day TABLE V Average weight per test groug in grams at the indi- Percent cate intervals following Percent control of inoculation weight coccidiosis increase of and eoccidial Active agent at dosage of 0.025 weight percent of lead 0 day 5 days 7 days test group organisms 1.2,3-trls (p-chlorobenzylidena)nmlnqgnmiidine 370 540 637 72 80 1,2,3-tris (p-chlorobenrylidcno)ominqguanidine, hydrochloride 410 608 730 78 92 1,2,3-015 (p-bromobenzylidene)aminoguunidlne 406 588 725 3 1,2,3-tris (g-bromobenzylidene)aminqguanldine, hydrochloride. i 411 613 733 94 Uninfecte checks (Control) 411 582 720 76 Infected checks (Control) 426 560 530 25 1 No coccidial organisms or disease. 1 All birds heavily infected with coceidial organisms.

' N-( -nitro-2-furfurylidene-3-amino-2-oxazolidone an uninfected check. The average weights of each test group at the aforementioned intervals and the percent weight increase for each test group are set fonh in table V.

EXAMPLE 6 Ninety parts by weight of l,2,3-tris[(p-chlorobenzylidene )aminolguanidine; l,2,3-tris[ (P-chlorobenzyseparately mechanically ground with bentonite to produce concentrate compositions containing 90 percent by weight of one of the guanidine compounds.

In a similar manner, additional feed supplements are prepared by grinding together 50 parts by weight of one of the guanidines identified hereinabove with 1 part of sorbitan menopalrnitate (Span 20) and 49 parts of attapulgite clay to produce compositions containing 50 percent by weight of one of the guanidine compounds.

In another operation, the guanidine compounds as identified in the foregoing two paragraphs are separately dispersed in 90 parts of cottonseed oil to prepare edible oil compositions containing one of the guanidine compounds.

These compositions are adapted to be administered to animals to supply the desired dosage of active compound or to be employed as concentrates and subsequently diluted with additional edible additaments, grain rations or animal feeds to produce animal feed compositions containing the desired amount of active agent.

EXAMPLE 7 In another operation, 20 parts by weight of one of 1,2,3- tris[ (p-chlorobenzylidene)amino]guanidine; l ,2,3-tris[ pchlorobenzylidene)amino1guanidine, hydrochloride; l,2,3- tris[(p-bromobenzylidene)aminojguanidine and l,2,3-tris[(pbromobenzylidene)aminolguanidine, hydrochloride are separately mechanically mixed with 80 parts of soybean meal to produce animal feed compositions containing 20 percent of one of the guanidine compounds. When these compositions are dispersed in commercial animal feed to produce animal feed compositions containing 0.01 percent by weight of one of the guanidine compounds and fed to chickens, results of weight gains and control of coccidial organisms substantially as described hereinbefore are obtained.

In a further embodiment, the guanidine-type compounds as employed in accordance with the present invention, or compositions containing the same, advantageously can be employed in the present methods in combination with one or more other feed additives including agents active against gastrointestinal parasites, as supplemental materials. Representative additives and agents include 2-sulfanilamidoquinoxaline, acetyl(p-nitrophenyl) sulfanilamide, sulfadimethylpyridine, 2,2'-methylene bis(4-chlorophenol), 4,4-isopropylidene bis(o-cresol), 5-nitro-2-furaldehyde semicarbazone, furoxone 4-hydroxyphenyl arsonic acid, p-aminobenzene arsonic acid, l-(4-amino-2-n-propyl-5-pyrimidinylmethyl)-2-pycolinum chloride hydrochloride), the complex of 4,4'-dinitrocarbanilide and 2-hydroxy-4,6-dimethylpyrimidine, 4,5imidazole 'dicarboxamide, methyl-4-acetamido-2-ethoxybenzoate, ox-

ytetracycline, chlorotetracycline, N-(4'-chlorophenyl)-7-oxabicyclo( 2.2. l )-heptane-2,3-dicarboxamide, methyl-4- acetamido-Z-ethoxybenzoate, tetraethyl thiuram disulfide, arsenosobenzene, 5-nitro-2-furaldehyde acetohydrazone, 2,2- dihydroxy-3,3,5,$'-tetrachlorodiphenylsulfide, 4,6-diamino- 2,2-dimethyl-l ,3,5-triazine hydrochloride, sulfamethazine, sulfamerazine, sulfadimidine, 2,4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidines, 2,4-diamino 5-(3,4-dichlorophenyl)- 6,6-diethyl-S,6-dihydrol ,3,5-triazines, 3.5-dinitrobenzamide,

3-nitrowater, 2.0 liters of ethanol and 3, 5-dinitro-o-toluamide, 2-chloro-4-nitrobenzamide and other analogues 2,4-diamino-5-aryl-6-alkylpyrimidines, 2,4- diamino-5-aryl-6,6-dialkyl-5 ,6-dihydro-l ,3 ,S-triazines, dinitrobenzamides, dinitrotoluamides and 3,5-dichloro-2,6- dimethylpyridinol.

ln representative operations, each of the feed additives identified in the preceding paragraph together with one of the guanidine compounds as shown in example 6 are mechanically mixed and ground with commercial poultry mash to produce animal feed compositions. In such operations, the materials are employed in amounts sufficient to provide feed compositions containing from about 0.0045 to about 0.0125 percent by weight of one of the feed additives identified in the preceding paragraph and from about 0.006 to about 0.0125 percent by weight of one of the guanidine compounds shown in example 6. These compositions are of excellent value in animal husbandry and are adapted to be fed to poultry to obtain maximum normal growth and to mitigate against the attack of protozoan organisms and particularly Eimeria organisms. The guanidine compounds employed in the practice of the present invention can be prepared as follows:

1, 2, 3-trls [(p-chlorobenzylldene)aminoIgusnldlne, hydrochloride To a flask containing 2,000 milliliters of a l:l water-ethanol mixture having dissolved therein ll2.0 grams (0.8 mole) of triaminoguanidine hydrochloride is added, under agitation, 20 milliliters of concentrated hydrochloric acid. Thereafter, 336.0 grams (2.4 moles) of p-chlorobenzaldehyde dissolved in 3,000 milliliters of ethanol is added thereto over a 30-minute period. This mixture is thereafter maintained under agitation at ambient temperature for about 20.0 hours. The reaction mixture is filtered and the crystals obtained are stirred in 2,500 milliliters of ethanol and the insolubles obtained by filtration. One-third of the filter cake obtained is stirred in 1,200 milliliters of diethylether and the solids removed by filtration. The l ,2,3-tris[ (p-chlorobenzylidene )amino ]guanidine. hydrochloride product is recovered in a yield of 124.0 grams after air drying. The identity of the product is confirmed by infrared spectroscopy (l.R.) and nuclear magnetic resonance spectra (NMR) analysis.

1, 2, 3-trls [(p-chlorobenzylidenemnunolguanldlne The remaining two-thirds filter cake from the ethanol wash in the previous synthesis is stirred in a mixture of 200 milliliters of concentrated ammonium hydroxide and 2.0 liters of water for about 20 hours. The mixture is filtered and the crystals so obtained are washed successively with 2.0 liters of 1,300 milliliters of diethylether. The l,2,3-tris[(p-chlorobenzylidene)amino] guanidine product is recovered in a yield of 202 grams after air drying. The identity of the product is confirmed by [.R. and NMR analysis.

This procedure is disclosed in Jour. Amer. Chem. Soc. 74, 5802 I952).

The p-bromo analogs are prepared in a similar procedure employing p-bromobenzaldehyde as the aldehyde reactant.

What is claimed is:

1. In the practice of animal husbandry for protection against coccidiosis, the method which comprises orally administering to animals a l,2,3-tris[(p-halobenzylidene)amino]guanidine compound or its hydrochloride salt, the guanidine compound being of the formula wherein X is chlorine or bromine, said compound being employed in an amount of from about three to about 1,000 parts per million of dietary intake.

2. The method as defined in claim 1 wherein said guanidine compound or its hydrochloride salt is in intimate admixture with an innocuous carrier.

3. The method of claim 2 wherein the guanidine compound is l,2,3-[(p-chlorobenzylidene)aminolguanidine.

4. The method of claim 2 wherein the active ingredient is l ,2, (p-chlorobenzylidene )amino] p-shlorobenzylidene)amino]guanidine, hydrochloride.

5. The method of claim 2 wherein the active ingredient is l ,2,3-[(p-bromobenzylidene )amino]guanidine.

6. The method of claim 2 wherein the active ingredient is l ,2,3-[(p-bromobenzylidene)amino]guanidine, hydrochloride.

7. The method of claim 1 wherein the guanidine compound or its salt is administered in an amount of from about 15 to about 250 parts per million gens of dietary intake.

8. The method of claim wherein the active ingredient is administered in an amount of from about l5 to about 250 parts per million parts of dietary intake.

LII

9. A composition comprising from about 5 to 98 percent by weight of a l,2,3-tris[(p-halobenzylidene)aminolguanidine compound or its hydrochloride salt, the guanidine compound being of the formula wherein X is chlorine or bromine.

11. The animal feed as defined in claim 10 and containing from 0.001 to 0.1 percent by weight of said l,2,3-tris[(phalobenzylidene)amino]guanidine compound or its hydrochloride salt.

" UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTIQN Patent NO. 3,62 l,2l 4 Dated 'goj b g Inventor(5) Graham T. Stevenson It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In column Table II at line 65, delete "O" and insert --0.0l25-- in the third line of the second column; insert O- in the third line of the third column.

In column 9, line 18, delete "(p-shlorobenzy-"; and in line 19 delete "lidene)amino]".

Signed and sealed this 1 1 th day of July 1 972.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents 

2. The method as defined in claim 1 wherein said guanidine compound or its hydrochloride salt is in intimate admixture with an innocuous carrier.
 3. The method of claim 2 wherein the guanidine compound is 1,2, 3-((p-chlorobenzylidene)amino)guanidine.
 4. The method of claim 2 wherein the active ingredient is 1,2,3-((p-chlorobenzylidene)amino)(p-chlorobenzylidene)amino)guanidine, hydrochloride.
 5. The method of claim 2 wherein the active ingredient is 1,2,3-((p-bromobenzylidene)amino)guanidine.
 6. The method of claim 2 wheRein the active ingredient is 1,2,3-((p-bromobenzylidene)amino)guanidine, hydrochloride.
 7. The method of claim 1 wherein the guanidine compound or its salt is administered in an amount of from about 15 to about 250 parts per million parts of dietary intake.
 8. The method of claim 2 wherein the active ingredient is administered in an amount of from about 15 to about 250 parts per million parts of dietary intake.
 9. A composition comprising from about 5 to 98 percent by weight of a 1,2,3-tris((p-halobenzylidene)amino)guanidine compound or its hydrochloride salt, the guanidine compound being of the formula
 10. A composition containing an animal feed and from about 0.001 to about 0.1 percent by weight of a 1,2,3-tris((p-halobenzylidene)amino)guanidine compound or its hydrochloride salt, the guanidine compound being of the formula
 11. The animal feed as defined in claim 10 and containing from 0.001 to 0.1 percent by weight of said 1,2,3-tris((p-halobenzylidene)amino)guanidine compound or its hydrochloride salt. 